boards & beyond: basic pharmacology slides
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Boards & Beyond: Basic Pharmacology Slides
Color slides for USMLE Step 1 preparationfrom the Boards and Beyond Website
Jason Ryan, MD, MPH
2021 Edition
Boards & Beyond provides a virtual medical school curriculm used by students around the globe to supplement their education and
prepare for board exams such as USMLE Step 1.
This book of slides is intended as a companion to the videos for easy reference and note-taking. Videos are subject to change
without notice. PDF versions of all color books are available via the website as part of membership.
Visit www.boardsbeyond.com to learn more.
Copyright © 2021 Boards and BeyondAll rights reserved.
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Enzymes ..................................................................1Enzyme Inhibitors ..............................................4Dose Response .....................................................6
Drug Elimination .............................................. 10Pharmacokinetics ............................................ 14
Table of Contents
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1
Michaelis-Menten Kinetics• At Vmax, enzymes saturated (doing all they can)• Only way to increase Vmax is to add enzyme
Michaelis-Menten Kinetics• Adding S →More P formation → Faster V• Eventually, reach Vmax
Michaelis-Menten Kinetics
V
[S]
V = Reaction velocityRate of P formation
Vmax
V = Vm* [S]Km + [S]
Enzymatic Reactions
Image courtesy of Wikipedia/U+003F
S + E ⇄ ES ⇄ E + P
Enzymatic Reactions
S
E
P
S + E ⇄ ES ⇄ E + P
EnzymesJason Ryan, MD, MPH
Enzymes
2
V = Vm* [S]Km + [S]
• Small Km → Vm reached at low concentration [S]• Large Km → Vm reached at high concentration [S]
Michaelis Constant (Km)
[S]
Vmax
Vmax/2
Km
[S]
Vmax
V = Vm* [S]Km + [S]
Michaelis Constant (Km)
Vmax/2
Km
[S] + [S] 2 [S] 2
Michaelis Constant (Km)
V = Vm * [S] = Vm * [S] = Vm
When V = Vm/2[S] = Km
Michaelis Constant (Km)
V = Vm * [S]Km + [S]
Key Points:1. Km has same units as [S]2. At some point on graph, Km must equal [S]
Michaelis-Menten Kinetics
V
[S]
V = Reaction velocityRate of P formation
Vmax
V = Vm* [S]Km + [S]
Enzyme Kinetics
[S]
Vmax
VmaxMore Enzyme
3
Lineweaver Burk Plot1V
1S
1 Vm
-1 Km
KmVm
Lineweaver Burk PlotV = Vm* [S]
Km + [S]
1 = Km + [S] = Km + [S]V Vm [S] Vm [S] Vm[S]
1 = C * 1 + 1V [S] Vm
Key Points• Km is characteristic of each substrate/enzyme• Vm depends on amount of enzyme present• Can determine Vm/Km from
• Michaelis Menten plot V vs. [S]• Lineweaver Burk plot 1/V vs. 1/[S]
V = Vm* [S]Km + [S]
Michaelis Constant (Km)• Small Km → Substrate binds easily at low [S]
• High affinity substrate for enzyme• Large Km → Low affinity substrate for enzyme
[S]
Vmax
Vmax/2
Km
4
Non-competitive Inhibitor
[S]
Vmax
VmaxWith inhibitor
Vmax/2
Vmax/2
Lower VmSame Km
Km
Competitive Inhibitor
[S]
Vmax
Vmax/2
Km
Normal
Km
Same VmHigher Km
Inhibitor
Enzyme Inhibitors
S
E
I
CompetitiveCompetes for same site as SLots of S will overcome this
S
E
P
Non-competitiveBinds different site S
Changes S binding siteS cannot overcome this
Effect similar to no enzyme
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Enzymatic Reactions
S
E
P
S + E ⇄ ES ⇄ E + P
Enzyme Inhibitors• Many drugs work through enzyme inhibition• Two types of inhibitors:
• Competitive• Non-competitive
Enzyme InhibitorsJason Ryan, MD, MPH
Enzyme Inhibitors
5
InhibitorsCompetitive
• Similar to S• Bind active site• Overcome by more S• Vm unchanged• Km higher
Non-competitive• Different from S• Bind different site• Cannot be overcome• Vm decreased• Km unchanged
Non-competitive Inhibitor1V
1S
1 Vm
-1 Km
Normal
Inhibitor
1 Vm
Competitive Inhibitor1V
1S
1 Vm
-1 Km
-1 Km
Normal
InhibitorCompetitive Inhibitor
1V
1S
1 Vm
-1 Km
Normal
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Dose-Response• Graded or quantal responses• Graded response
• Example: Blood pressure• Can measure “graded” effect with different dosages
• Quantal response• Drug produces therapeutic effect: Yes/No• Example: Number of patients achieving SBP<140mmHg• Can measure “quantal” effect by % patients responding to dose
Dose-Response• For many drugs we can measure response as we
increase the dose• Can plot dose (x-axis) versus response (y-axis)
Pain Control
Analgesia
Dose (mg)
Morphine
Aspirin
Potency• Amount of drug needed for given effect
• Drug A produces effect with 5mg• Drug B produces same effect with 50mg• Drug A is 10x more potent than drug B
• More potent not necessarily superior• Low potency only bad if dose is so high it’s hard to
administer
Efficacy• Maximal effect a drug can produce
• Morphine is more efficacious than aspirin for pain control
Dose-ResponseJason Ryan, MD, MPH
Dose Response
7
Non-competitive Antagonists
Log [Dose]
Effect
Emax
E50
ReceptorAgonist Receptor Agonist +
Non-Competitive Antagonist
E50
EC50
MaxEffect
Competitive Antagonists
Log [Dose]
Effect
Emax
E50
ReceptorAgonist Receptor Agonist +
Competitive Antagonist
Graded Dose Response Curve
Log [Dose]
Effect
Emax
E50
EMax/EfficacyB>A
A B Efficacy
Emax
Graded Dose Response Curve
Log [Dose]
Effect
Emax
E50
EC50/PotencyA > B > C
A B C
Potency
Graded Dose Response Curve
Log [Dose]
Effect
Emax
E50
1 10 100
↓EC50 = ↑Potency
Graded Dose Response Curve
Dose
Effect
Emax
E50
10 20 30 40 50 60
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Partial AgonistSingle Dose Agonist With Increasing Partial Agonist
Log [Dose Partial Agonist]
Response
100%AgonistResponse
PartialAgonist
Response0%
TotalResponse
Partial AgonistSingle Dose Agonist With Increasing Partial Agonist
Log [Dose Partial Agonist]
%Binding
100%Agonist Partial
Agonist
0%
Partial AgonistsAgonist or Partial Agonist Given Alone
Log [Dose]
Effect
Emax
FullAgonist
Partial Agonist
MaxEffect
Effect similar to agonist plus NC antagonist
Partial Agonists• Similar structure to agonists• Produce less than full effect
Spare Receptors
Log [Dose]
Effect
Agonist +Low Dose
Non-CompetitiveAntagonist
Agonist +High Dose
Non-CompetitiveAntagonist
Emax
Source: Basic and Clinical Pharmacology, Katzung
Spare Receptors• “Spare” receptors: Activate when others blocked• Maximal response can occur even in setting of blocked
receptors• Experimentally, spare receptors demonstrated by
using irreversible antagonists• Prevents binding of agonist to portion of receptors• High concentrations of agonist still produce max response
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Low TI Drugs• Often require measurement of levels to avoid toxicity• Warfarin• Digoxin• Lithium• Theophylline
TherapeuticWindow
Therapeutic Window
Log [Dose]
% Patients
100%
50%
LD50
MinimumEffective
Dose
MinimumToxicDose
Therapeutic Index• Measurement of drug safety
Therapeutic Index = LD50ED50
Quantal Dose Response Curve
Log [Dose]
% Patients
Therapeutic Response Adverse Response100%
50%
ED50 LD50/TD50
Quantal Dose Response Curve
Log [Dose]
% Patients
Therapeutic Response100%
50%
ED50
Partial Agonists• Pindolol/Acebutolol
• Old anti-hypertensives• Activate beta receptors but to less degree that norepinephrine• “Intrinsic sympathomimetic activity” (IMA)• Lower BP in hypertensive patients• Can cause angina through vasoconstriction
• Buprenorphine• Partial mu-opioid agonist• Treatment of opioid dependence
• Clomiphene• Partial agonist of estrogen receptors hypothalamus• Blocks (-) feedback; ↑LH/FSH• Infertility/PCOS
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First Order Elimination
Time (hr) Amount (g) Change (g) %0 10 1001 5 5 502 2.5 2.5 253 1.25 1.25 12.5
Zero Order Elimination
Time (hr) Amount (g) Change (g) %0 20 1001 15 5 75%2 10 5 50%3 5 5 25%
First Order Elimination• Rate varies with concentration of drug• Percent (%) change with time is constant (half life)• Most drugs 1st order elimination
Time
Plas
ma C
once
ntra
tion
Rate = C * [Drug]1
4units
2units1units
Zero Order Elimination• Constant rate of elimination per time• No dependence/variation with [drug]• No constant half life
Time
Plas
ma C
once
ntra
tion
5units
5units
5units
Rate = 5 * [Drug]0
• Ethanol• Phenytoin• Aspirin
Elimination
Time
Plas
ma C
once
ntra
tion
Time
Plas
ma C
once
ntra
tion
Zero Order First Order
Drug EliminationJason Ryan, MD, MPH
Drug Elimination
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Urine pH• Urine pH affects drug excretion• Weak acids: Alkalinize urine to excrete more drug• Weak bases: Acidify urine to excrete more drug
Weak Base: BOH <-> B+ + OH-
Weak Acid: HA <-> A- + H+
Urine pH• Drugs filtered by glomerulus• Ionized form gets “trapped” in urine after filtration• Cannot diffuse back into circulation
Weak Base: BOH <-> B+ + OH-
Weak Acid: HA <-> A- + H+
Urine pH• Many drugs are weak acids or weak bases
Weak Acid: HA <-> A- + H+
Weak Base: BOH <-> B+ + OH-
Capacity-dependent Elimination• Follows Michaelis-Menten kinetics• Rate of elimination = Vmax · C / (Km + C)• “Saturatable” → High C leads to Vmax rate• When this happens zero order elimination occurs• Three classic drugs:
• Ethanol• Phenytoin• Aspirin
Flow-dependent Elimination• Some drugs metabolized so quickly that blood flow to
organ (usually liver) determines elimination• These drugs are “high extraction” drugs• Example: Morphine• Patients with heart failure will have ↓ clearance
Special Types of Elimination• Flow-dependent• Capacity-dependent
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P450 DrugsSome Examples
Inducers• Chronic EtOH• Rifampin• Phenobarbital• Carbamazepine• Griseofulvin• Phenytoin
Inhibitors• Isoniazid• Erythromycin• Cimetidine• Azoles• Grapefruit juice• Ritonavir (HIV)
Cytochrome P450• Inhibitors are more dangerous
• Can cause drug levels to rise• Cyclosporine, some macrolides, azole antifungals
• Luckily, many P450 metabolized drugs rarely used• Theophylline, Cisapride, Terfenadine
• Some clinically relevant possibilities• Some statins + Inhibitor → Rhabdo• Warfarin
Cytochrome P450• Intracellular enzymes• Metabolize many drugs (Phase I)• If inhibited → drug levels rise• If induced → drug levels fall
Phase I Metabolism• Reduction, oxidation, or hydrolysis reactions• Often creates active metabolites• Two key facts to know:
• Phase I metabolism can slow in elderly patients• Phase I includes cytochrome P450 system
Drug Metabolism• Many, many liver reactions that metabolize drugs• Liver “biotransforms” drug• Usually converts lipophilic drugs to
hydrophilic products• Creates water-soluble metabolites for excretion
• Reactions classified as Phase I or Phase II
Examples• Weak acid drugs
• Phenobarbital, aspirin• Sodium bicarbonate to alkalinize urine in overdose
• Weak base drugs• Amphetamines, quinidine, or phencyclidine• Ammonia chloride (NH4Cl) to acidify urine in overdose• Historical: Efficacy not established, toxicity severe acidosis
13
Slow Acetylators• Genetically-mediated ↓ hepatic N-acetyltransferase• Acetylation is main route isoniazid (INH) metabolism• Also important sulfasalazine (anti-inflammatory)• Procainamide and hydralazine
• Can cause drug-induced lupus• Both drugs metabolized by acetylation• More likely among slow acetylators
Phase II Metabolism• Conjugation reactions
• Glucuronidation, acetylation, sulfation• Makes very polar inactive metabolites
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First Pass Metabolism• Oral drugs absorbed → liver• Some drugs rapidly metabolized on 1st pass• Decreases amount that reaches circulation• Can be reduced in liver disease patients
Bioavailability (F)• Intravenous dosing
• F = 100%• Entire dose available to body
• Oral dosing• F < 100%• Incomplete absorption• First pass metabolism
Bioavailability (F)• Fraction (%) of drug that reaches systemic circulation
unchanged• Suppose 100mg drug given orally• 50mg absorbed unchanged• Bioavailability = 50%
Drug Administration• Enteral
• Uses the GI tract• Oral, sublingual, rectal
• Parenteral• Does not use GI tract• IV, IM, SQ
• Other• Inhalation, intranasal, intrathecal• Topical
Pharmacokinetics• Absorption• Distribution• Metabolism• Excretion• All impact drug’s ability to achieve desired resultPharmacokinetics
Jason Ryan, MD, MPH
Pharmacokinetics
15
Volume of Distribution (Vd)• Useful for determining dosages• Example:
• Effective [drug]=10mg/L• Vd for drug = 10L• Dose = 10mg/L * 10L = 100mg
Volume of Distribution (Vd)
PlasmaConcentration
Time
ExtrapolateC0
C0
Vd = Amount InjectedC0
Volume of Distribution (Vd)
Vd = Total Amount In BodyPlasma Concentration
Vd = 10g = 20L0.5g/L
Determining Fluid Volume
1gram 1Liter Fluid 1g/L
1gram Unknown Volume 1g/L
Volume of Distribution (Vd)• Theoretical volume a drug occupies • Determined by injecting known dose and measuring
concentration
Bioavailability (F)
PlasmaConcentration
Time
IV
Oral
Bioavailability = AUC oral x 100 AUC IV
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Clearance• Mostly occurs via liver or kidneys• Liver clearance
• Biotransformation of drug to metabolites• Excretion of drug into bile
• Renal clearance• Excretion of drug into urine
Clearance• Volume of blood “cleared” of drug• Volume of blood that contained amount of drug• Number in liters/min (volume flow)
Cx = Excretion RatePx
Hypoalbuminemia• Liver disease• Nephrotic syndrome• Less plasma protein binding• More unbound drug →moves to peripheral
compartments• ↑Vd• Required dose of drug may change
Protein Binding• Many drugs bind to plasma proteins (usually albumin)• This may hold them in the vascular space• Lowers Vd
Volume of Distribution (Vd)• Drugs restricted to vascular compartment: ↓Vd
• Large, charged molecules• Often protein bound• Warfarin: Vd = 9.8L
• Drugs that accumulate in tissues: ↑↑Vd• Small, lipophilic molecules• Often uneven distribution in body• Chloroquine: Vd = 13000L
Fluid Compartments
Total BodyWater
36L
12LExtracellular
24LIntracellular
3LPlasma
9L Interstitial
Vd ↑ when drug distributes to more fluid compartments
(blood, ECF, tissues)
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Half-lifeHalf-Life• Time required to change amount of drug in the body
by one-half• Usually time for [drug] to fall 50%• Depends on Vd and Clearance (CL)
t1/2 = 0.7 * VdCL
Cl (l/min) = Dose (g)
Clearance
Time
Plas
ma C
once
ntra
tion
AUC (g*min/l)
Area Under Curve (AUC)
Clearance
Cx = Vd * Ke
Ke = CxVd
Clearance• Can also calculate from Vd• Need elimination constant (Ke)• Implications:
• Higher Vd, higher clearance• Supposed 10g/hour removed from body• Higher Vd→ Higher volume holding 10g → Higher clearance
Cx = Vd * Ke
Clearance• In liver or kidney disease clearance may fall• Drug concentration may rise• Toxicity may occur• Dose may need to be decreased
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Steady State• Dose administered = amount drug eliminated• Takes 4-5 half lives to reach steady state
0
0.2
0.4
0.6
0.8
1
1.2
0 0.2 0.4 0.6 0.8 1 1.2
Half-Lives
Dose
Loading Dose• Target concentration * Vd• Suppose want 5g/l • Vd = 10L• Need 5 * 10 = 50grams loading dose• Divide by F if bioavailability <100%
Loading Dose = [Drug] * VdF
Maintenance Dose• * If Bioavailability is <100%, need to increase dose to
account for this
Dose Rateoral = Target DoseF
Target Dose = 25g/minBioavailability = 50%
Dose Rate = 25/0.5 = 50g/min
Maintenance DoseDose Rate = Elimination Rate
= [Drug] * Clearance
Dose Rate = [5g/l] * 5L/min= 25 g/min
Calculating Doses• Maintenance dose
• Just enough drug to replace what was eliminated• Loading dose
• Given when time to steady state is very high• Get to steady state more quickly• When t1/2 is very high
• In kidney/liver disease, maintenance dose may fall• Less eliminated per unit time• Less needs to be replaced with each dose
• Loading dose will be unchanged
Steady State• Dose administered = amount drug eliminated• Takes 4-5 half lives to reach steady state
0
5
10
15
20
25
0 1 2 3 4 5 6 7
Half-Lives
Dose
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Key Points• Volume Distribution = Amt injected / [Drug]• Clearance = 0.7 * Vd / t12• 4-5 half lives to get to steady state• Maintenance dose = [Steady State] * CL / F• Loading dose = [Steady State] * Vd / F
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